Carcinogenesis Advance Access originally published online on August 3, 2006
Carcinogenesis 2007 28(1):215-222; doi:10.1093/carcin/bgl139
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Deoxycholate induces mitochondrial oxidative stress and activates NF-
B through multiple mechanisms in HCT-116 colon epithelial cells
1 Department of Cell Biology & Anatomy, College of Medicine University of Arizona, Tucson, AZ 85724-5044, USA
2 Arizona Cancer Center, University of Arizona Tucson, AZ, USA
3 Department of Internal Medicine, College of Medicine University of Arizona, Tucson, AZ, USA
4 Southern Arizona Veterans Affairs Health Care System, Tucson AZ, USA
*To whom correspondence should be addressed: Tel: +1 520 885 0662; Fax: +1 520 626 2097 Email: cpayne{at}email.arizona.edu
Nuclear factor kappa B (NF-
B) is a redox-associated transcription factor that is involved in the activation of survival pathways. We have previously shown that deoxycholate (DOC) activates NF-B in hepatocytes and colon epithelial cells and that persistent exposure of HCT-116 cells to increasing concentrations of DOC results in the constitutive activation of NF-B, which is associated with the development of apoptosis resistance. The mechanisms by which DOC activates NF-B in colon epithelial cells, and whether natural antioxidants can reduce DOC-induced NF-B activation, however, are not known. Also, it is not known if DOC can generate reactive oxygen species within mitochondria as a possible pathway of stress-related NF-B activation. Since we have previously shown that DOC activates the NF-B stress-response pathway in HCT-116 cells, we used this cell line to further explore the mechanisms of NF-B activation. We found that DOC induces mitochondrial oxidative stress and activates NF-B in HCT-116 cells through multiple mechanisms involving NAD(P)H oxidase, Na+/K+-ATPase, cytochrome P450, Ca++ and the terminal mitochondrial respiratory complex IV. DOC-induced NF-B activation was significantly (P < 0.05) inhibited by pre-treatment of cells with CAPE, EGCG, TMS, DPI, NaN3, EGTA, Ouabain and RuR. The NF-B-activating pathways, induced by the dietary-related endogenous detergent DOC, provide mechanisms for promotion of colon cancer and identify possible new targets for chemoprevention.
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